PROJECT SUMMARY Clinical criteria for late-onset Alzheimer's disease (LOAD) excludes individuals with ?substantial cerebrovascular disease? but as many as up 70% of patients with LOAD have cerebrovascular pathology in addition to amyloid plaques and neurofibrillary tangles at postmortem examination. Whether cerebrovascular damage represents a cause of LOAD, an additional brain insult or whether cerebrovascular pathology interacts with genetic factors remains unknown. The Washington Heights and Inwood, Columbia Aging Project is a large, epidemiological investigation of dementia in a multi-ethnic community in northern Manhattan, New York. The investigators have estimated the ethnic and sex-specific rates of late onset Alzheimer's disease and mild cognitive impairment, conducted longitudinal assessments of cognitive performance, health and lifestyle factors, mood, ADLs, blood pressure, anthropometry, several blood-based biomarkers, genome wide association studies (GWAS), structural MRI and is in the process of completing whole exome sequencing (WES) in 4100 individuals. We intend to take advantage of this multi-ethnic, longitudinal cohort to test hypotheses concerning how genetic variants, cardiovascular and cerebrovascular risk factors and cerebrovascular disease predispose to LOAD and whether these relationships differ by ethnic group. We intend to address three critical questions: 1) Do genetic variants influence both LOAD and cardio-cerebrovascular risk factors independently or do they interact? 2) Do cardio- cerebrovascular risk factors lead to cerebrovascular pathology, present on brain MRI, which in turn simply lowers the threshold for clinical onset of dementia? 3) Are genetic variants unrelated to cardio-cerebrovascular risk factors and simply exacerbate the effects of cerebrovascular pathology leading to LOAD? Or could the reverse be true, that silent cerebrovascular disease exacerbates the effects of genetic variants on LOAD risk? LOAD and cerebrovascular disease are likely to be part of a continuum in which the onset and clinical manifestations of dementia are jointly determined. Thus, investigating the relationship between genes harboring variants, vascular risk factors, cerebrovascular disease and LOAD would advance our understanding of this complex disease process and will help develop potential targets for treatments or preventive measures that are more precise for the individual patient.